Pediatric Annals

Bone Marrow Transplantation for Genetic Diseases

Robertson Parkman, MD

Abstract

Bone marrow transplantation has an established role in the treatment of children with immunological, hematological, and oncological diseases. There has been increasing acceptance of bone marrow transplantation for the treatment of genetic diseases. Genetic diseases involving erythrocyte dysfunction (eg, thalassemia and sickle cell disease), granulocyte dysfunction (eg, infantile agranulocytosis and chronic granulomatous disease), platelet abnormalities (eg, Wvskott-Aldrich syndrome and congenital megakaryocytosis), and inborn errors of metabolism have been cured or stabilized by allogeneic hone marrow transplantation.1

Successful bone marrow transplantation results in the engraftment of both donor lymphoid and hematopoietic stem cells. Following transplantation, all elements of the immune and hematopoietic system including fixed tissue macrophages (eg, osteoclasts, Kupffer's cells, and most likely microglial cells) are of donor origin. The first genetic disease to be successfully treated by bone marrow transplantation was severe combined immunodeficiency, an abnormality of the lymphoid stem cell.2

Diseases caused by abnormalities of the hematopoietic stem cell are the present focus of bone marrow transplantation for genetic diseases. The first genetic disease involving the hematopoietic stem cell to be cured by bone marrow transplantation was the WiskottAldrich syndrome, in which affected males have eczema, immunodeficiency, and dysfunctional platelets with reduced size. In 1977, two patients with the Wiskott-Aldrich syndrome were successfully transplanted following pretransplant preparation with antithymocyte serum and total body irradiation to eradicate the patients' defective lymphoid and hematopoietic stem cells.3 Following successful donor lymphoid and hematopoietic stem cell engraftment, the patients developed normal immunological and platelet function. The initial use of total body irradiation to eradicate abnormal hematopoietic stem cells has been replaced by the use of busulfan, which has less toxicity and equivalent efficacy.4 Patients with genetic diseases are now routinely prepared for transplantation with cyclophosphamide to eliminate their lymphoid stem cells and busulfan to eliminate their hematopoietic stem cells.

ERYTHROID DISORDERS

The genetic disease for which bone marrow transplantation has had the greatest use is thalassemia.5 The first successful transplant for thalassemia was performed in 1980. Since then, transplantation for thalassemia has had increasing use, primarily in Italy. Initially, Lucarelli et al reported an 84% disease-free survival rate in patients transplanted with histocompatible bone marrow following pretransplant chemotherapy with busulfan and cyclophosphamide. The principal reasons for failure were lack of hematopoietic engraftment, chronic graft-versus-host disease, and transplant-related deaths. More recently, a good risk group of patients (under the age of 5 with an absence of preexisting liver disease) had a 94% disease-free survival rate.6

In the United States, thalassemia patients are usually treated with chelation therapy and hypertransfusion. The Italians have chosen, as a public health policy, to treat thalassemia with bone marrow transplantation. Their results demonstrate that histocompatible bone marrow transplants can be successfully used to treat the majority of patients with a genetic disease if patients are appropriately selected. The improvement in the results with thalassemia is a result of the transplantation of younger patients who have a lower risk of graft-versushost disease and less preexisting end organ damage.

Based on the successful treatment of thalassemia major with bone marrow transplantation, bone marrow transplantation for the treatment of patients with sickle cell anemia has been undertaken. The initial bone marrow transplants for sickle cell anemia were performed in patients with an underlying neoplastic process. Recent attempts have had the primary goal of treating the patient's sickle cell anemia.7 Significant end organ damage can occur in some sickle cell anemia patients before clinical signs are present. Bone marrow transplantation for sickle cell anemia may have increasing use in the United States if high-risk patients can be identified at a young age.

GRANULOCYTE DISORDERS

Bone marrow transplantation has been used to treat…

Bone marrow transplantation has an established role in the treatment of children with immunological, hematological, and oncological diseases. There has been increasing acceptance of bone marrow transplantation for the treatment of genetic diseases. Genetic diseases involving erythrocyte dysfunction (eg, thalassemia and sickle cell disease), granulocyte dysfunction (eg, infantile agranulocytosis and chronic granulomatous disease), platelet abnormalities (eg, Wvskott-Aldrich syndrome and congenital megakaryocytosis), and inborn errors of metabolism have been cured or stabilized by allogeneic hone marrow transplantation.1

Successful bone marrow transplantation results in the engraftment of both donor lymphoid and hematopoietic stem cells. Following transplantation, all elements of the immune and hematopoietic system including fixed tissue macrophages (eg, osteoclasts, Kupffer's cells, and most likely microglial cells) are of donor origin. The first genetic disease to be successfully treated by bone marrow transplantation was severe combined immunodeficiency, an abnormality of the lymphoid stem cell.2

Diseases caused by abnormalities of the hematopoietic stem cell are the present focus of bone marrow transplantation for genetic diseases. The first genetic disease involving the hematopoietic stem cell to be cured by bone marrow transplantation was the WiskottAldrich syndrome, in which affected males have eczema, immunodeficiency, and dysfunctional platelets with reduced size. In 1977, two patients with the Wiskott-Aldrich syndrome were successfully transplanted following pretransplant preparation with antithymocyte serum and total body irradiation to eradicate the patients' defective lymphoid and hematopoietic stem cells.3 Following successful donor lymphoid and hematopoietic stem cell engraftment, the patients developed normal immunological and platelet function. The initial use of total body irradiation to eradicate abnormal hematopoietic stem cells has been replaced by the use of busulfan, which has less toxicity and equivalent efficacy.4 Patients with genetic diseases are now routinely prepared for transplantation with cyclophosphamide to eliminate their lymphoid stem cells and busulfan to eliminate their hematopoietic stem cells.

ERYTHROID DISORDERS

The genetic disease for which bone marrow transplantation has had the greatest use is thalassemia.5 The first successful transplant for thalassemia was performed in 1980. Since then, transplantation for thalassemia has had increasing use, primarily in Italy. Initially, Lucarelli et al reported an 84% disease-free survival rate in patients transplanted with histocompatible bone marrow following pretransplant chemotherapy with busulfan and cyclophosphamide. The principal reasons for failure were lack of hematopoietic engraftment, chronic graft-versus-host disease, and transplant-related deaths. More recently, a good risk group of patients (under the age of 5 with an absence of preexisting liver disease) had a 94% disease-free survival rate.6

In the United States, thalassemia patients are usually treated with chelation therapy and hypertransfusion. The Italians have chosen, as a public health policy, to treat thalassemia with bone marrow transplantation. Their results demonstrate that histocompatible bone marrow transplants can be successfully used to treat the majority of patients with a genetic disease if patients are appropriately selected. The improvement in the results with thalassemia is a result of the transplantation of younger patients who have a lower risk of graft-versushost disease and less preexisting end organ damage.

Based on the successful treatment of thalassemia major with bone marrow transplantation, bone marrow transplantation for the treatment of patients with sickle cell anemia has been undertaken. The initial bone marrow transplants for sickle cell anemia were performed in patients with an underlying neoplastic process. Recent attempts have had the primary goal of treating the patient's sickle cell anemia.7 Significant end organ damage can occur in some sickle cell anemia patients before clinical signs are present. Bone marrow transplantation for sickle cell anemia may have increasing use in the United States if high-risk patients can be identified at a young age.

GRANULOCYTE DISORDERS

Bone marrow transplantation has been used to treat granulocyte disorders characterized by abnormalities of granulocyte differentiation and function. Diverse diseases including infantile agranulocytosis, chronic granulomatous disease, and Chédiak-Higashi syndrome have been successfully transplanted.1 The recent demonstration that some disorders of myeloid differentiation can be treated by exogenous recombinant growth factors (G-CSF for infantile agranulocytosis) means that bone marrow transplantation is no longer indicated for some granulocyte disorders.8 The introduction of growth factors to treat disorders of granulocyte function demonstrates that bone marrow transplantation may be an intermediate stage of treatment for some genetic diseases.

OSTEOPETROSIS

Patients with infantile osteopetrosis have been cured following successful donor bone marrow engraftment.9 Although all circulating leukocytes were of donor origin 1 month following transplantation, increased calcium excretion and the remodeling of the abnormal bony architecture did not begin until 4 to 6 months following transplantation. Following transplantation, bone biopsies demonstrated that the osteoclasts were of donor origin; thus, osteoclasts are of bone marrow origin, and the primary defect in osteopetrosis is an intrinsic abnormality of the osteoclasts. The principal problem associated with the transplantation of patients with osteopetrosis is the identification of patients early in the course of their disease before irreversible neurological damage (blindness or deafness) occurs.

INBORN ERRORS OE METABOLISM

Inborn errors of metabolism represent the area of greatest dispute concerning the role of bone marrow transplantation for the treatment of genetic diseases. The first metabolic disease to be successfully corrected by histocompatible bone marrow transplantation was Gaucher's disease.10 Following pretransplant cytoablation, successful engraftment of donor lymphoid and hematopoietic stem cells was achieved with circulating leukocytes of donor origin with normal levels of functional glucocerebrosidase. Whereas erythroid and myeloid disorders are cured within 1 month following transplantation, delays were seen in the clinical improvement following transplantation for Gauchers disease. The delayed improvement was caused by the significantly slower turnover of tissue macrophages than that of circulating erythroid and myeloid elements. Thus, it required 6 months for the abnormal Gaucher tissue macrophages to turnover and be replaced by tissue macrophages derived from the normal donor hematopoietic stem cells. Bone marrow transplantation is a potential therapy for the subset of Gaucher's disease patients in whom splenectomy is inadequate to maintain normal hematopoiesis. Exogenous enzyme therapy is presently under evaluation to determine if enzyme replacement therapy will be superior to bone marrow transplantation.

The inborn errors of metabolism for which the greatest clinical experience has occurred is the mucopolysaccharidoses. Hurler's syndrome, caused by detects in the enzyme a-iduronidase, was the first mucopolysaccharide defect to be transplanted.11 In Hurler's syndrome, successful bone marrow engraftment leads to the presence of circulating lymphoid and myeloid cells of donor origin with normal levels of enzyme. Following donor engraftment, the patient's non-central nervous system (CNS) symptoms are reversed with a decrease in hepatomegaly and a reduction in corneal clouding.

An area of dispute is the effect of successful engraftment on the patient's CNS function. In animal models, successful bone marrow engraftment results in enzymatically normal donor cells being detectable within the CNS. Debate exists as to whether the bone marrow-derived cells are present within the CNS as a consequence of CNS degeneration or the turnover of hematopoietically-derived cells including microglial cells. However, the presence of normal donor-derived cells within the CNS will not repair preexisting CNS damage. The presence of enzymatically normal donor cells may retard further CNS deterioration. Neuropsychiatrie evaluation of Hurler syndrome patients suggests that the decline in the patient's developmental quotient ceases 4 to 6 months following successful transplantation, a time at which microglial cells of donor origin may be detected.12 Thus, patients with normal or slightly reduced developmental quotients may have stabilization of their CNS function. If, however, a patient's CNS function is significantly reduced prior to transplantation, improvement cannot be expected.

Following successful donor engraftment, all circulating leukocytes are enzymatically normal. Because the abnormal accumulation of mucopolysaccharides occurs within the nonlymphohematopoietic cells of the patient, it is necessary for the enzyme produced by the engrafted donor cells to gain access to the substrate accumulations. The transport of enzyme from normal to abnormal cells can be documented by in vitro coculture experiments.13 The coculturing of fibroblasts from mucopolysaccharidosis patients and normal individuals results in the degradation of substrate in the abnormal fibroblasts. Presumably similar transport mechanisms exist in vivo. In fact, diseases in which the coculture of cells does not result in correction of the metabolic abnormalities are usually not corrected by bone marrow transplantation. No in vitro correction occurs when cells from patients with Pompe's disease are cocultured, and no clinical improvement nor a decrease in glycogen accumulation occurs following bone marrow transplantation.

Patients with other forms of mucopolysaccharidosis including Hunter's syndrome, Sanfilippo B disease, and Maroteaux-Lamy syndrome have been transplanted with resolution of some of the non-CNS manifestations of the disease. Of note is the feet that the bony abnormalities in Maroteaux-Lamy syndrome have not resolved following donor engraftment possibly because donor-derived enzyme cannot enter the chondrocytes.14

Bone marrow transplantation has been used to treat lipidoses that involve the CNS. Patients with both adrenoleukodystrophy (ALD) and metachromatic leukodystrophy (MLD) have been transplanted.15·16 Metachromatic leukodystrophy patients have had correction of their CNS abnormalities as measured by normalization of their magnetic resonance imaging (MRI) results following transplantation. Patients with advanced ALD have died during the transplant procedure. However, patients transplanted in an early stage of ALD have shown improvement in their neuropsychiatrie function and MRl abnormalities. Successful donor engraftment appears to modify the natural history of the patient's disease if the transplants are performed early in the disease course. As in the case of mucopolysaccharidoses, it is important that patients with lipidoses be transplanted before irreversible CNS damage occurs.

GENE THERAPY

At present, bone marrow transplantation for genetic diseases is restricted to the 25% of patients who have a histocompatible sibling. With the establishment of the National Bone Marrow Transplant Donor Program, it is possible to identify unrelated histocompatible individuals.17 Patients with a variety of inborn errors of metabolism have now been successfully transplanted with unrelated matched donors. Recipients of matched unrelated donor transplants have a higher incidence of graft-versus-host disease than recipients of histocompatible sibling transplants. Nevertheless, matched unrelated donor transplants represent a potential therapeutic modality for patients with genetic diseases who do not have histocompatible family donors.

Even with the use of matched unrelated donors, it is extremely difficult to find histocompatible donors for many patients. Therefore, investigators are studying the role of gene therapy to treat genetic diseases. In gene therapy, the normal gene for the patient's disease would be inserted into the appropriate target cell (ie, hematopoietic stem cells for thalassemia, hepatocytes for phenylketonuria, and lymphoid stem cells for adenosine deaminase deficiency). The normal gene would be inserted in vitro and the corrected cells returned to the patient. Ultimately, the normal gene might be inserted in vivo. Prerequisites for gene therapy include:

* identification of the genetic basis for the disease,

* identification of the normal gene for the disease,

* the insertion of the normal gene into the appropriate target cell with high efficiency,

* the regulated expression of the normal gene product, and

* the determination that the introduction of the normal gene does not result in deleterious consequences, including neoplastic transformation or the induction of neoantigens.18

Initial attempts at gene therapy have used the insertion of the gene for adenosine deaminase into the peripheral blood T lymphocytes of children with severe combined immunodeficiency caused by adenosine deaminase deficiency. These attempts, however, will not result in long-term cure of the patients because the normal gene is being inserted into cells without the capacity for self-renewal. The use of gene therapy as curative therapy will require that the normal gene be inserted into stem cells that have the capacity for self-renewal.

CONCLUSION

Bone marrow transplantation has an established role in the treatment of genetic abnormalities of the lymphoid and hematopoietic stem cells. Debate still exists concerning the use of bone marrow transplantation to treat inborn errors of metabolism. In the future, gene therapy may permit treating all patients with genetic diseases.

REFERENCES

1. Lenarsky C, Kahn DB, Weinberg KI. Parkman R. Bone marrow transplantation for genetic diseases. Hematol Oncol Clin North Am. 1990;4:589-602.

2. Gatti RA, Meuwissen HJ, Alien HU et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;ii:1366-1369.

3. Parkman R, Rappeport J, Geha R, et al. Complete correction of the Wiskolt-Aldrich syndrome by allogeneic bone mamw transplantation. N Eng! J Med 1978;298:921-927.

4. Kapoor N, Kirkpatrick D, Blaese RM, et al. Reconstitution of normal megakaryocytopoiesis and immunological functions in Wiskotl-Aldtich syndrome by marrow transplantation following myeloablation and immunosuppression with busulfan and cyclophosphamide. Blood. 1981;57:692-696.

5. Lucarelli O, Galiroberti M, Polchi E et al. Marrow transplantation in patients with advanced thalassemia. N Engl J Med. 1987;316:1050-1055.

6. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med. 1990;3 22:417-421

7. Verymylen C, Minane J, Robles EF, et al. Bone marrow transplantation in five children with sickle cell anemia. Lancet. 1988;i:1427-1428.

8. Bonilla MA, Gillio AR Ruggiero M. et al. Effects of recombinant human granulocyte colony-stimulating tactor on neutropenia in patients with congenital agranulocytosis. N Engl J Med. 1989;320:1574-1580.

9. Coccia PF, Krivit W, Cervenka J, et al. Successful bone marrow transplantation fot infantile malignant osteoperrosis. N Engl J Med. 1980;302:701-708.

10. Rappeport JM, Ginns EI. Bone marrow transplantation in severe Gaucher's disease. N Engl J Med. 1984;311:84-88.

11. Hobbs JR, Hugh-Jones K, Barren AJ, et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone marrow transplantation. Lancet. 1981;ii:709-712.

12. Hugh-Jones K. Psychomotor development of children with mucopolysaccharidosis Type 1-H following bone marrow transplantation. In: Krivit W, Paul NW, eds. Bone Morrow Tronsplanlalion for Treatment of Lysosamal Storage Disease:. VoI 22. New York, NY: Alan R. Liss; 1986:25-29.

13. Neufeld EE Lessons from genetic disorders of lysosomes. Tht Harvey Lecture Series, 75. New ibrk, NY: Academic Press; 1981:41-60.

14. Krivit W, Pierpont ME, Ayaz K. et al. Bone-mamw transplantation in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Biochemical and clinical status 24 months after transplantation. N Engl J Med. 1984:31 1:l606-i611.

15. Aubourg P, Blanche S, Jambaque I, et al. Reversal of early neurologic and neuroradiologic; manifestations of X-linked adenuleukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322:1860-1866.

16. Krivit W, Shapiro E, Kennedy W, et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl Med. 1990;322:28-32.

17. McGlave PB, Beatty P, Ash R, Hows JM. Therapy for chronic nnelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases. Blood. 1990:75:1728-1732.

18. Miller DA. Progress toward human gene therapy. Blood. 1990;76:271-278.

10.3928/0090-4481-19911201-07

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